Inhibition of Monoamine Oxidase-B by 5H-Indeno[1,2-c]pyridazines: Biological Activities, Quantitative Structure-Activity Relationships (QSARs) and 3D-QSARs

A large series (66 compounds) of indeno[1,2-c]pyridazin-5-ones (IPs) were synthesized and tested on their monoamine oxidase-A (MAO-A) and MAO-B inhibitory activity. All of the tested compounds acted preferentially on MAO-B displaying weak (nonmeasurable IC50 values) to high (submicromolar IC50 value...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1995-09, Vol.38 (19), p.3874-3883
Main Authors: Kneubuehler, Silvia, Thull, Ulrike, Altomare, Cosimo, Carta, Vincenco, Gaillard, Patrick, Carrupt, Pierre-Alain, Carotti, Angelo, Testa, Bernard
Format: Article
Language:English
Subjects:
Biological and medical sciences
Computer Graphics
Magnetic Resonance Spectroscopy
Medical sciences
Models, Molecular
Molecular Conformation
Monoamine Oxidase - metabolism
Monoamine Oxidase Inhibitors - chemistry
Monoamine Oxidase Inhibitors - pharmacology
Neuropharmacology
Pharmacology. Drug treatments
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Pyridazines - chemical synthesis
Pyridazines - chemistry
Pyridazines - pharmacology
Spectrum Analysis
Structure-Activity Relationship
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Summary:A large series (66 compounds) of indeno[1,2-c]pyridazin-5-ones (IPs) were synthesized and tested on their monoamine oxidase-A (MAO-A) and MAO-B inhibitory activity. All of the tested compounds acted preferentially on MAO-B displaying weak (nonmeasurable IC50 values) to high (submicromolar IC50 values) activities. The most active compound was p-CF3-3-phenyl-IP (IC50 = 90 nM). Multiple linear regression analysis of the substituted 3-phenyl-IPs yielded good statistical results (q2 = 0.74; r2 = 0.86) and showed the importance of lipophilic, electronic, and steric properties of the substituents in determining inhibitory potency. Various comparative molecular field analysis studies were performed with different alignments and including the molecular lipophilicity potential. This led to a model including the steric, electrostatic and lipophilicity fields and having a good predictive value (q2 = 0.75; r2 = 0.93).
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00019a018